The results of a recent study suggest an intriguing link between mitochondrial genetics and health. This study used C57BL-nuclear-genome matched conplastic mice, where one strain carries mitochondria from the C57BL background (BL6C57) and the other strain carries the mitochondria from the NZ background (BL6NZB). The authors reported that mice carrying NZB mitochondrial DNA (mtDNA) are healthier and show significant differences in longevity despite sharing the same nuclear genome as the BL6C57 mice. Since the mtDNA of NZB and C57BL6 mice vary by only a few mutations, their findings suggest that small changes in mitochondirla genetics can cause large difference in health and longevity. They reported that these differences correlated with a number of changes that are consistent with the activation of axes of the mitochondrial unfolded protein response (UPRmt) identified in the Germain's lab. One axis is regulated by SIRT3 and FOXO3a, both key regulators of aging. Another axis is regulated by the estrogen receptor alpha (ER?). We also recently reported that small differences in mtDNA sequence can lead to differential activation of the axes of the UPRmt and also that their activation varies between males and females. Our central hypothesis is that the differences between the conplastic mice are due to the ability mtDNA of the BL6NZB to activate the UPRmt and will differ not only between males and females. To test this hypothesis, we propose the following three aims: Specific aim 1: Assess the activation of the UPRmt in tissues in the BL6C57 males and females versus BL6NZB males and females congenic mice. Specific aim 2: Test whether deleting key genes of each UPRmt nodes abolishes the health benefit of the BL6NZB conplastic mice. Specific aim 3: Assess whether interventions known to increase SIRT3, FOXO3a or ER? improve the health and longevity of BL6C57 conplastic mice.